Heterocycles useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119 of U.S. Provisional application Ser. No. 60/685,971 filed May 31, 2005, the entire contents of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. They play key roles in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and airway. As such they play key roles in a variety of disease states such as epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain (ee, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R. Cummins, et al. (2000) “Voltage-gated sodium channels and the molecular pathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonic disorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr Opin Neurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81), multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E. Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia” Am J Physiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al. (2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinence and visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See, Hurley, S. C. (2002) “Lamotrigine update and its use in mood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypes show tissue specific localization and functional differences (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TTX binding (See, Noda, M., H. Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheral nervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Na isoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain, Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nM Neurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic, injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μM Arrhythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread, most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminals disorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG & TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine for neuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See, Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See, Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 and Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment of neuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to be useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflects, at least in part, an increase in the excitability of high-threshold primary afferent neurons innervating the site of injury. Voltage sensitive sodium channels activation is critical for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that modulation of NaV currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal root ganglion (DRG) neurons. The TTX-resistant current is insensitive to micromolar concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a more depolarized activation threshold when compared to other voltage-gated sodium channels. TTX-resistant sodium currents are primarily restricted to a subpopulation of sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium currents are expressed almost exclusively in neurons that have a small cell-body diameter; and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique region of the TTX-resistant sodium channel (NaV1.8) resulted in a significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S. G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20). More recently, a knockout mouse line was generated by Wood and colleagues, which lacks functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal's response to the inflammatory agent carrageenan (ee, Akopian, A. N., V. Souslova, et al. (1999) “The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways” Nat Neurosci 2(6): 541-8). In addition, deficit in both mechano- and thermoreception were observed in these animals. The analgesia shown by the Nav1.8 knockout mutants is consistent with observations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitro electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L. Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons” Nature 379(6562): 257-62). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (ee Lai, J., M. S. Gold, et al. (2002) “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons” Methods Enzymol 314: 201-13). NaV1.8 protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense treatment prevents the redistribution of NaV1.8 along the nerve and reverses neuropathic pain. Taken together the gene-knockout and antisense data support a role for NaV1.8 in the detection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channel distribution and subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas expression of the TTX sensitive subunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell, et al. (1999) “Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain.” Pain 83(3): 591-600.) The timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models subsequent to nerve injury. The biophysics of the NaV1.3 channel is distinctive in that it shows very fast repriming after inactivation following an action potential. This allows for sustained rates of high firing as is often seen in the injured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons” J Neurosci 21(16): 5952-61). NaV1.3 is expressed in the central and peripheral systems of man. NaV1.9 is similar to NaV1.8 as it is selectively localized to small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Fang, X., L. Djouhri, et al. (2002). “The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons.” J Neurosci 22(17): 7425-33). It has a slow rate of inactivation and left-shifted voltage dependence for activation (See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodium channel with unique properties” Trends Neurosci 25(5): 253-9). These two biophysical properties allow NaV1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of NaV1.9 expressing cells is in the −55 to −50 mV range compared to −65 mV for most other peripheral and central neurons. This persistent depolarization is in large part due to the sustained low-level activation of NaV1.9 channels. This depolarization allows the neurons to more easily reach the threshold for firing action potentials in response to nociceptive stimuli. Compounds that block the NaV1.9 channel may play an important role in establishing the set point for detection of painful stimuli. In chronic pain states, nerve and nerve ending can become swollen and hypersensitive exhibiting high frequency action potential firing with mild or even no stimulation. These pathologic nerve swellings are termed neuromas and the primary Na channels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T., L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry” Acta Neurochir (Wien) 144(8): 803-10; discussion 810). NaV1.6 and NaV1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX sensitive component seen in these cells. NaV1.7 in particular my therefore be a potential pain target in addition to it's role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) “Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) “A missense mutation of the Na⁺ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) have been linked to epilepsy conditions including febrile seizures. There are over 9 genetic mutations in NaV1.1 associated with febrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiac arrhythmias. A gene defect in NaV1.5 that produces a larger noninactivating component to the current has been linked to long QT in man and the orally available local anesthetic mexilitine has been used to treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels.” J Clin Invest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in the clinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3, and Guay, D. R. (2001) “Adjunctive agents in the management of chronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold, M. S. (1999) “Tetrodotoxin-resistant Na⁺ currents and inflammatory hyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathic pain (ee Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain” Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotrigine monotherapy for control of neuralgia after nerve section” Acta Anaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H., R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na⁺ channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels” J Clin Invest 99(7): 1714-20); neuroprotection (ee Taylor, C. P. and L. S, Narasimhan (1997) “Sodium channels and therapy of central nervous system diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain.” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed for the study of sodium channel modulators for numerous different pain indications. E.g., malignant chronic pain, see, Kohase, H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase, H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignant chronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994; 42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav Brain Res. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al., Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y. et al., J Neurosci Methods. 2001; 104(2):191-8); Neuropathic low back pain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B., et al., J Neurosci Methods. 2004; 137(2):283-9; neuropathic low back pain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B., et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial pain syndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002; 16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46); fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995; 15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain Res Mol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including, abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000; 119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., Neurosci Lett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., et al., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N., et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol. 2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark, Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al., J Neurophysiol. 1999; 81(2):479-93); tension headache, including, cluster headaches (see, Costa, A., et al., Cephalalgia. 2000; 20(2):85-91); chronic neuropathic pain, including, post-herpetic neuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al., Clin J Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993; 53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, Ned Tijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004; 107(1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35); trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp Brain Res. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda, M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensory neuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003; 12(15):1917-25); peripheral nerve injury (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett & Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149; Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas (see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor & Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal and distal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27); radiculopathy (see, Devers & Galer, (see, Clin J Pain. 2000; 16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapy induced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996; 73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomy pain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain (Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cord injury pain (see, Hains, B. C., et al., Exp Neurol. 2000; 164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., et al., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome (see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; Xantos D et al., J Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W. E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain. 1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can J Anaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see, Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J., et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; joint pain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22); mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000; 85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay, M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain, including, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; etc (see, Giambernardino, M. A., et al., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain (see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvic pain, renal colic pain, acute obstetric pain, including, labor pain (see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, including, endometriosis (see, Cason, A. M., et al., Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cell anemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000; 119(5):1373-81); breakthrough pain; orofacial pain, including, sinusitis pain, dental pain (see, Nusstein, J., et al., J Endod. 1998; 24(7):487-91; Chidiac, J. J., et al., Eur J Pain. 2002; 6(1):55-67); multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci. 1999; 162(2):162-8; Waxman, Stephen G. et al, PNAS 2000; 97(21): 11598-602); pain in depression (see, Greene B, Curr Med Res Opin. 2003; 19(4):272-7); leprosy pain; behcet's disease pain; adiposis dolorosa (see, Devillers & Oranje, Clin Exp Dermatol. 1999; 24(3):240-1); phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain (see, Legroux-Crespel, E., et al., Ann Dermatol Venereol. 2003; 130(4):429-33); Fabry's disease pain (see, Germain, D. P., J Soc Biol. 2002; 196(2):183-90); Bladder and urogenital disease, including, urinary incontinence (see, Berggren, T., et al., J Urol. 1993; 150(5 Pt 1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al., Urology. 2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura, N., et al., J. Neurosci. 2001; 21(21):8690-6); interstitial cyctitis (IC) (see, Giannakopoulos & Campilomatos, Arch Ital Urol Nefrol Androl. 1992; 64(4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); and prostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith, I. M., et al., J Urol. 2001; 166(1):323-8).

Voltage-gated calcium channels are membrane-spanning, multi-subunit proteins that open in response to membrane depolarization, allowing Ca entry from the extracellular milieu. Calcium channels were initially classified based on the time and voltage-dependence of channel opening and on the sensitivity to pharmacological block. The categories were low-voltage activated (primarily T-type) and high-voltage activated (L, N, P, Q or R-type). This classification scheme was replaced by a nomenclature based upon the molecular subunit composition, as summarized in Table B (Hockerman G H, Peterson B Z, Johnson B D, Catterall W A. 1997. Annu Rev Pharmacol Toxicol 37: 361-96; Striessnig J. 1999. Cell Physiol Biochem 9: 242-69). There are four primary subunit types that make up calcium channels—α₁, α₂δ, β and γ (See, e.g., De Waard et al. Structural and functional diversity of voltage-activated calcium channels. In Ion Channels, (ed. T. Narahashi) 41-87, (Plenum Press, New York, 1996)). The α₁ subunit is the primary determinant of the pharmacological properties and contains the channel pore and voltage sensor (Hockerman et al., 1997; Striessnig, 1999). Ten isoforms of the α₁ subunit are known, as indicated in Table I below. The α₂δ subunit consists of two disulfide linked subunits, α₂, which is primarily extracellular and a transmembrane δ subunit. Four isoforms of α₂δ are known, α₂δ-1, α₂δ-2, α₂δ-3 and α₂δ-4. The β subunit is a non-glycosylated cytoplasmic protein that binds to the α₁ subunit. Four isoforms are known, termed β₁ to β₄. The γ subunit is a transmembrane protein that has been biochemically isolated as a component of Ca_(v)1 and Ca_(v)2 channels. At least 8 isoforms are known (γ₁ to γ₈) [Kang M G, Campbell K P. 2003. J Biol Chem 278: 21315-8]. The nomenclature for voltage-gated calcium channels is based upon the content of the α₁ subunit, as indicated in Table I. Each type of α₁ subunit can associate with a variety of β, α₂δ or γ subunits, so that each Ca_(v) type corresponds to many different combinations of subunits.

TABLE B Cav Nomenclature α₁ subunit Pharmacological name Ca_(v)1.1 α_(1S) L-type Ca_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4 α_(1F) Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3 α_(1E) R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3 α_(1I) T-type

Ca_(v)2 currents are found almost exclusively in the central and peripheral nervous system and in neuroendocrine cells and constitute the predominant forms of presynaptic voltage-gated calcium current. Presynaptic action potentials cause channel opening and neurotransmitter release is steeply dependent upon the subsequent calcium entry. Thus, Ca_(v)2 channels play a central role in mediating neurotransmitter release.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for the peptide toxins ω-conotoxin-MVIIC and ω-conotoxin-GVIA, respectively, and these peptides have been used to determine the distribution and function of each channel type. Ca_(v)2.2 is highly expressed at the presynaptic nerve terminals of neurons from the dorsal root ganglion and neurons of lamina I and II of the dorsal horn (Westenbroek R E, Hoskins L, Catterall W A. 1998. J Neurosci 18: 6319-30; Cizkova D, Marsala J, Lukacova N, Marsala M, Jergova S, et al. 2002. Exp Brain Res 147: 456-63). Ca_(v)2.2 channels are also found in presynaptic terminals between second and third order interneurons in the spinal cord. Both sites of neurotransmission are very important in relaying pain information to the brain.

Pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage. Severe thermal, mechanical, or chemical inputs have the potential to cause severe damage to the organism if unheeded. Acute pain serves to quickly remove the individual from the damaging environment. Acute pain by its very nature generally is short lasting and intense. Inflammatory pain on the other had may last for much longer periods of time and it's intensity is more graded. Inflammation may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion. Inflammatory pain is mediated by an “inflammatory soup” that consists of substance P, histamines, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and neurotransmitter release. The third class of pain is neuropathic and involves nerve damage that results in reorganization of neuronal proteins and circuits yielding a pathologic “sensitized” state that can produce chronic pain lasting for years. This type of pain provides no adaptive benefit and is particularly difficult to treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmet medical need. Millions of individuals suffer from severe pain that is not well controlled by current therapeutics. The current drugs used to treat pain include NSAIDS, COX2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been particularly difficult to treat as it does not respond well to opioids until high doses are reached. Gabapentin is currently the favored therapeutic for the treatment of neuropathic pain although it works in only 60% of patients where it shows modest efficacy. The drug is however very safe and side effects are generally tolerable although sedation is an issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic pain is provided by studies with ziconotide (also known as ω-conotoxin-MVIIA), a selective peptide blocker of this channel (Bowersox S S, Gadbois T, Singh T, Pettus M, Wang Y X, Luther R R. 1996. J Pharmacol Exp Ther 279: 1243-9; Jain K K. 2000. Exp. Opin. Invest. Drugs 9: 2403-10; Vanegas H, Schaible H. 2000. Pain 85: 9-18). In man, intrathecal infusion of Ziconotide is effective for the treatment of intractable pain, cancer pain, opioid resistant pain, and neuropathic pain. The toxin has an 85% success rate for the treatment of pain in humans with a greater potency than morphine. An orally available antagonist of Ca_(v)2.2 should have similar efficacy without the need for intrathecal infusion. Ca_(v)2.1 and Ca_(v)2.3 are also in neurons of nociceptive pathways and antagonists of these channels could be used to treat pain.

Antagonists of Ca_(v)2.1, Ca_(v)2.2 or Ca_(v)2.3 should also be useful for treating other pathologies of the central nervous system that apparently involve excessive calcium entry. Cerebral ischaemia and stroke are associated with excessive calcium entry due to depolarization of neurons. The Ca_(v)2.2 antagonist ziconotide is effective in reducing infarct size in a focal ischemia model using laboratory animals, suggesting that Ca_(v)2.2 antagonists could be used for the treatment of stroke. Likewise, reducing excessive calcium influx into neurons may be useful for the treatment of epilepsy, traumatic brain injury, Alzheimer's disease, multi-infarct dementia and other classes of dementia, amyotrophic lateral sclerosis, amnesia, or neuronal damage caused by poison or other toxic substances.

Ca_(v)2.2 also mediates release of neurotransmitters from neurons of the sympathetic nervous system and antagonists could be used to treat cardiovascular diseases such as hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, and congestive heart failure.

Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects. Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and/or calcium channels. These are compounds of formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION I. General Description of Compounds of the Invention

In one embodiment, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

 is a single or double bond;

X₁ and X₂ each is independently ═CR³—, ═N—, —O—, —S—, or —NR³—;

X₃ is R³ or a lone pair of electrons;

provided that X₁, X₂, and N(X₃), taken together with the intervening carbon atoms form a 5-membered heteroaryl ring;

W is halo, OR′, SR′, N(R′)₂, NRC(O)R′, S(O)₂N(R′)₂, OC(O)R′, OC(O)N(R′)₂, NR(S(O)₂R′, OP(O)(OR′)₂, OP(O)₂OR′, OP(O)(R′)₂, CHF₂, CH₂F, or CF₃;

R¹ and R², taken together with the nitrogen atom, form a 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen, wherein said ring is optionally substituted at one or more substitutable ring atoms with z independent occurrences of —R⁴, wherein z is 0-5;

y is 0-5;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independently selected from —R′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group;

each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, the following compounds are excluded:

(i) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W, together with R⁵ and y is 2,4-difluorophenyl, then R¹ and R² taken together is not optionally substituted 2,3-dihydro-1H-isoindol-1-one-2-yl;

(ii) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W, together with R⁵ and y is 2,4-dichlorophenyl, then R¹ and R² taken together is not optionally substituted 2,3-dihydro-1H-indol-1-yl or an optionally substituted tetracyclic ring system;

(iii) when X₁ is S, X₂ is ═CMe-, X³ is a lone pair of electrons, W, together with R⁵ and y is 2,4-dimethoxyphenyl, then R¹ and R² taken together is not an optionally substituted pyrrol-1-yl ring fused to an optionally substituted pyridazine ring;

(iv) when X₁ is S, X₂ is ═CR³—, and X³ is a lone pair of electrons, then R¹ and R² taken together is not an optionally substituted pyrrol-1-yl;

(v) when X₁ is ═N—, X² is O, X³ is a lone pair of electrons, and W is halo, then R¹ and R² taken together is not 1,4-diazabicyclo[3.2.2]nonan-1-yl;

(vi) when X₁ is S, X₂ is ═CH—, X³ is a lone pair of electrons, W, together with R⁵ and y is 2-chlorophenyl, then R¹ and R² taken together is not an optionally substituted imidazol-1-yl;

(vii) when X₁ is ═N—, X₂ is ═CH—, X₃ is H, y is 0, and W is NHSO₂Ar′, wherein Ar′ is an optionally substituted phenyl, then R¹ and R² taken together is not 2-butanamido-pyrrolidin-1-yl;

(viii) when X₁ is ═N—, X₂ is ═CH— or ═C(Cl)—, X₃ is H, and W is NHSO₂Ar′, wherein Ar′ is an optionally substituted phenyl or NHC(O)R, wherein R is an optionally substituted aliphatic, then R¹ and R² taken together is not 3-[(dimethylamino)sulfonyl]amino-morpholin-4-yl or 2-(methoxycarbonyl)amino-4,5-dichloro-1H-imidazol-1-yl;

(ix) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, W is OH or OMe, then R¹ and R² taken together is not 3,4-dihydro-2-(1H)-quinozolin-3-one-2-yl;

(x) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, and W is halo or OR′, then R¹ and R² taken together is not an optionally substituted 2-imino-thiazolidin-4-one-3-yl;

(xi) when X₁ is S, X₂ is ═CH—, and X₃ is a lone pair of electrons, then R¹ and R² taken together is not an optionally substituted azetidin-2-one-1-yl;

(xii) when X₁ is S, X₂ is ═CR³—, X₃ is a lone pair of electrons, and W is OH or halo, then R¹ and R² taken together is not an optionally substituted 3,4-dihydro-(3H)-quinazolin-4-one-3-yl;

(xiii) when X₁ is S, X₂ is ═CR³—, X₃ is a lone pair of electrons, and W is halo, OMe, or NHSO₂Ar′, wherein Ar′ is an optionally substituted phenyl, then R¹ and R² taken together is not an optionally substituted ring selected from thiazolidin-4-one-3-yl, 2,4-dioxo-imidazolin-1-yl, 4,5-dihydro-5-oxo-(1H)-imidazol-1-yl, or azetidin-1-yl;

(xiv) when X₁ is S, X₂ is ═CH—, X₃ is a lone pair of electrons, and W is halo, then R¹ and R² taken together is not 1,2,3,4-tetrahydro-(1H)-quinazolin-2,4-dioxo-3-yl; and

(xv) when X₁ is ═N—, X₂ is ═CR³—, X₃ is H, then R¹ and R² taken together is not 3,5-dioxo-1,2,4-triazolidin-4-yl, 2,5-dioxo-pyrrolidin-1-yl, or 2,5-dioxo-imidazolidin-1-yl.

2. Compounds and Definitions

Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise specified herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; —R^(o); —OR^(o); —SR^(o); phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN; —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂; —(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); or —CH═CH(Ph), optionally substituted with R^(o); wherein each independent occurrence of R^(o) is selected from hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph), or, notwithstanding the definition above, two independent occurrences of R^(o), on the same substituent or different substituents, taken together with the atom(s) to which each R^(o) group is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Unless otherwise specified herein, optional substituents on the aliphatic group of R^(o) are selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise specified herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group.

Unless otherwise specified herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R⁺, on the same substituent or different substituents, taken together with the atom(s) to which each R⁺ group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Unless otherwise specified herein, optional substituents on the aliphatic group or the phenyl ring of R⁺ are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoing Cl₄aliphatic groups of R⁺ is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

As detailed above, in some embodiments, two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein), are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein), are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R^(o))₂, where both occurrences of R^(o) are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of

these two occurrences of R^(o) are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings can be formed when two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.

Unless otherwise specified herein, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon or a nitrogen by a ¹⁵N nitrogen are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

3. Description of Exemplary Compounds

In one embodiment, X₁, X₂, and X₃ taken together form a ring selected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring i. Or, said ring is ring ii. Or, said ring is ring iii.

In another embodiment, X₁, X₂, and X₃ taken together form a ring selected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring iv. Or, said ring is ring v. Or, said ring is ring vi.

In another embodiment, X₁, X₂, and X₃ taken together form a ring selected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring vii. Or, said ring is ring viii. Or, said ring is ring ix.

In another embodiment, X₁, X₂, and X₃ taken together form a ring selected from:

In one embodiment, X₁, X₂, and X₃ taken together form ring x. Or, said ring is ring xi. Or, said ring is ring xii.

In another embodiment X₁, X₂, and X₃ taken together form ring xiii:

In one embodiment, X₁, X₂, and X₃ are taken together to form ring ii, W is halo or OR′, R¹ and R², taken together with the nitrogen atom, form a 6-membered monocyclic saturated ring having 0-1 additional heteroatoms selected from nitrogen, wherein said ring is optionally substituted at one or more substitutable ring atoms with z independent occurrences of —R⁴, wherein z is 0.

In another embodiment, X₁, X₂, and X₃ are taken together to form ring ii, W is halo or OR′, and R¹ and R² taken together, form ring mm or nn.

In another embodiment, X₁, X₂, and X₃ are taken together to form ring ii, W is halo or OR′, and R¹ and R² form a ring shown below:

In another embodiment, X₁, X₂, and X₃ are taken together to form ring viii or xi, W is halo or OR′, R¹ and R², taken together with the nitrogen atom, form a 6-membered monocyclic saturated ring having 0-1 additional heteroatoms selected from nitrogen, wherein said ring is optionally substituted at one or more substitutable ring atoms with z independent occurrences of —R⁴, wherein z is 0.

In another embodiment, X₁, X₂, and X₃ are taken together to form viii or xi, W is halo or OR′, and R¹ and R² taken together, form ring mm or nn.

In one embodiment, R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-8-membered monocyclic, saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein the ring formed by R¹ and R² taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5.

In another embodiment, R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-8-membered monocyclic, saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen, wherein the ring atom in each of R¹ and R² adjacent to said nitrogen atom is a —CH₂—; wherein the ring formed by R¹ and R² taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5.

In one embodiment of the present invention, R¹ and R² taken together form an azetidinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form a pyrrolidinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form a piperidinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form a piperazinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form a morpholinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form a thiomorpholinyl ring:

In another embodiment of the present invention, R¹ and R² taken together form an azepanyl ring:

In another embodiment of the present invention, R¹ and R² taken together form an azocanyl ring:

In one embodiment, R¹ and R² together form a ring (ii) or (jj) as shown below:

wherein:

G₁ is —N—, —CH—NH—, or —CH—CH₂—NH—;

each of m₁ and n₁ is independently 0-3, provided that m₁+n₁ is 2-6;

p₁ is 0-2;

z is 0-4;

each R^(XX) is hydrogen, C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R^(XX) is optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3; provided that both R^(XX) are not simultaneously hydrogen;

R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or —PO(R′);

each occurrence of R¹¹ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment of the present invention, one R^(XX) is hydrogen and the other R^(XX) is not hydrogen.

In another embodiment of the present invention, both R^(XX) are not hydrogen.

In one embodiment of the present invention, p₁ is 0. Or, p₁ is 1. Or, p₁ is 2.

In one embodiment of the present invention, m₁ and n₁ each is 1. Or, m₁ and n₁ each is 2. Or, m₁ and n₁ each is 3.

In one embodiment of the present invention, R^(XX) is C₁₋₆ aliphatic group, wherein R^(XX) is optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3. Or, R^(XX) is C1-C6 alkyl group optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3.

In one embodiment of the present invention, R^(XX) is C1-C6 alkyl group.

In another embodiment of the present invention, R^(XX) is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R^(XX) is optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3.

In another embodiment, R^(XX) is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R^(XX) is optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3.

In another embodiment, R^(XX) is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R^(XX) is optionally substituted with w₁ independent occurrences of —R¹¹, wherein w₁ is 0-3.

In another embodiment, R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or —PO(R′).

Or, R^(YY) is hydrogen.

In another embodiment, R^(YY) is —COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or —PO(R′).

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred R include methyl, ethyl, propyl, or butyl.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In yet another embodiment, p₁ is 0, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In yet another embodiment, p₁ is 0, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In one embodiment of the present invention, R¹ and R² together form a ring as shown below:

In one embodiment, R^(XX) is C1-C6 alkyl.

In one embodiment, R^(XX) is methyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

In one embodiment, R¹ and R² taken together form ring (kk) as shown below:

G₃ is —N—, or CH; each of m₂ and n₂ is independently 0-3, provided that m₂+n₂ is 2-6; p₂ is 0-2; provided that when G₃ is N, then p₂ is not 0; q₂ is 0 or 1; z is 0-4; Sp is a bond or a C1-C6 alkylidene linker, wherein up to two methylene units are optionally and independently replaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—, —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—; ring B is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w₂ independent occurrences of —R¹², wherein w₂ is 0-4;

each occurrence of R¹² is independently Q-Rx; wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, G₃ is N. Or, G₃ is CH.

In one embodiment, p₂ is 0. Or, p₂ is 1. Or, p₂ is 2.

In another embodiment, q₂ is 0. Or, q₂ is 1.

In one embodiment, p₂ is 1, and q₂ is 1.

In another embodiment, G₃ is CH, p₂ is 0, and q₂ is 1.

In one embodiment, m₂ and n₂ each is 1. Or, m₂ and n₂ each is 2.

In another embodiment, Sp is selected from —O—, —S—, or —NR′—. In one embodiment, Sp is —O—. Or, Sp is —NR′—. Or, Sp is —NH—.

In one embodiment, ring B is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w₂ independent occurrences of —R¹² wherein w₂ is 0-4.

In another embodiment, ring B is a 4-8 membered, saturated, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w₂ independent occurrences of —R¹², wherein w₂ is 0-4.

In yet another embodiment, ring B is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w₂ independent occurrences of —R¹², wherein w₂ is 0-4.

In one embodiment, w₂ is 0.

In another embodiment, ring B is tetrahydrofuranyl.

In yet another embodiment,

i) Sp is a bond, 0, or —CH₂—;

ii) p₂ is 1;

iii) R is hydrogen; and

iv) n₂ and m₂ are both simultaneously 1 or 2.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred R include methyl, ethyl, propyl, or butyl.

In one embodiment, R¹ and R² taken together form a ring of formula (kk-i) or formula (kk-ii):

According to one embodiment, ring B is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w₂ independent occurrences of —R², wherein w₂ is 0-4.

According to another embodiment, R is hydrogen. Or, R is hydrogen and ring B is tetrahydrofuranyl.

According to yet another embodiment, Sp is a bond, —O—, or —O—CH₂—.

In one embodiment, R¹ and R² taken together form a ring (ll):

each of m₃ and n₃ is independently 0-3, provided that m₃+n₃ is 2-6; z is 0-4; Sp³ is —O—, —S—, —NR′—, or a C1-C6 alkylidene linker, wherein up to two methylene units are optionally and independently replaced by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—, —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—, provided that Sp³ is attached to the carbonyl group through an atom other than carbon; ring B₃ is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w₃ independent occurrences of —R¹³, wherein w₃ is 0-4;

each occurrence of R¹³ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′S₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, Sp³ is selected from —O—, —S—, or —NR′—. Or, Sp is —O—. Or, Sp³ is —O—CH₂—. In another embodiment, Sp³ is —NR′—. Or, Sp³ is —NH—. Or, Sp³ is —NH—CH₂—.

In one embodiment, each of m₃ and n₃ is 1. In another embodiment, each of m₃ and n₃ is 2.

In one embodiment, ring B₃ is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w₃ independent occurrences of —R¹³, wherein w₃ is 0-4.

In another embodiment, ring B₃ is a 4-8 membered, saturated, monocyclic heterocyclic ring having 1-4 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w₃ independent occurrences of —R³, wherein w₃ is 0-4.

In yet another embodiment, ring B₃ is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w₃ independent occurrences of —R³, wherein w₃ is 0-4.

In one embodiment, w₃ is 0.

In another embodiment, ring B₃ is tetrahydrofuranyl.

In yet another embodiment, Sp³ is a bond, 0, or —O—CH₂—; R is hydrogen; and n₃ and m₃ are both simultaneously 1 or 2.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred R include methyl, ethyl, propyl, or butyl.

In another embodiment, z is 0.

According to one embodiment, ring B₃ is a 5-6 membered, saturated, monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w₃ independent occurrences of —R³, wherein w₃ is 0-4.

According to another embodiment, R is hydrogen. Or, R is hydrogen and ring B₃ is tetrahydrofuranyl.

According to yet another embodiment, Sp₃ is a bond, —O—, —O—CH₂—, or —NH—CH₂.

In one embodiment, R¹ and R² taken together form a ring (mm):

each of m₄ and n₄ is independently 0-3, provided that m₄+n₄ is 2-6; p₄ is 1-2; R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3;

each occurrence of R¹⁴ is independently Q-Rx; wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, p₄ is 1. Or, p₄ is 2.

In one embodiment, m₄ and n₄ each is 1. Or, m₄ and n₄ each is 2. Or, m₄ and n₄ each is 3.

In one embodiment, R^(YZ) is C1-C6 alkyl, optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3. In another embodiment, R^(YZ) is C1-C4 alkyl group optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3. Or, R^(Y) is C1-C6 alkyl group.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred R groups include methyl, ethyl, propyl, or butyl.

In another embodiment, R¹ and R² taken together form a ring (mm-1):

each of m₄ and n₄ is independently 0-3, provided that m₄+n₄ is 2-6; p₄ is 0-2; R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3;

wherein up to two methylene units in R^(YZ) are optionally replaced with —NR—, —O—, —CO₂—, —OCO—, —NRCO—, —CONR—, —CO—, —SO₂NR—, or —NRSO₂—;

each occurrence of R¹⁴ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of Rx is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In one embodiment, p₄ is 1. Or, p₄ is 2.

In another embodiment, p₄ is 0.

In one embodiment, m₄ and n₄ each is 1. Or, m₄ and n₄ each is 2. Or, m₄ and n₄ each is 3.

In one embodiment, R^(YZ) is C1-C6 alkyl, optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3. In another embodiment, R^(YZ) is C1-C4 alkyl group optionally substituted with w₄ independent occurrences of —R⁴, wherein w₄ is 0-3. Or, R^(Y) is C1-C6 alkyl group.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred R groups include methyl, ethyl, propyl, or butyl.

In another embodiment, the present invention provides a compound of formula mm-2 or mm-3:

In one embodiment of formula mm-2 and mm-3, R^(YZ) is an unsubstituted C₁-C₆ aliphatic group.

In one embodiment of formula mm-2, R^(YZ) is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₃, —CH(CH₃)₃, —CH₂CH(CH₃)₂, or —CH₂C(CH₃)₃.

In one embodiment of formula mm-3, R^(YZ) is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, or —CH₂C(CH₃)₃.

In one embodiment, R¹ and R² are taken together to form a ring (nn):

In one embodiment, G₁ is —N—. Or, G₁ is —CH—NH—. Or, G₁ is —CH—CH₂—NH—.

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In yet another embodiment, p₄ is 0, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In one embodiment, R¹ and R² are taken together to form a ring (pp):

In another embodiment, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In yet another embodiment, p₄ is 0, R^(YY) is hydrogen, one R^(XX) is hydrogen, and the other R^(XX) is C1-C6 alkyl.

In one embodiment of the present invention, W is OR′. In another embodiment, W is OH.

In one embodiment of the present invention, W is SR′. In another embodiment, W is SH.

In one embodiment of the present invention, W is N(R′)₂. In another embodiment, W is NHR′. Or, W is NH₂.

In one embodiment of the present invention, W is CHF₂, or CH₂F. In one embodiment, W is CHF₂. In another embodiment, W is CH₂F.

In another embodiment, W is CF₃.

In one embodiment of the present invention, z is 0-5. In another embodiment, z is 1-3. In yet another embodiment, z is 1-2. In yet another embodiment, z is 1.

In one embodiment of the present invention, R⁴ is independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In another embodiment of the present invention, R⁴ is independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In one embodiment of the present invention, R¹ and R², taken together is optionally substituted azetidin-1-yl (aa), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In another embodiment, R¹ and R², taken together is optionally substituted azetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRSO₂R′. In another embodiment, R¹ and R², taken together is optionally substituted azetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRCOOR′. In another embodiment, R¹ and R², taken together is optionally substituted azetidin-1-yl (aa), wherein z is 1 and R⁴ is —NRCOR′.

In yet another embodiment, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (bb), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′.

In another embodiment, R¹ and R², taken together is optionally substituted piperidin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted piperidin-1-yl (cc), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In another embodiment, R¹ and R², taken together is optionally substituted piperidin-1-yl (cc), wherein z is 1 and R⁴ is —NRSO₂R′. In another embodiment, R¹ and R², taken together is optionally substituted piperidin-1-yl (cc), wherein z is 1 and R⁴ is —NRCOOR′.

In yet another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 and R⁴ is —SOR′. In another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 and R⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted piperazin-1-yl (dd), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —SOR′. In another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted morpholin-1-yl (ee) or thiomorpholin-1-yl (ff), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —SOR′. In another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted azepan-1-yl (gg), wherein z is 1 and R⁴ is —COR′.

In yet another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —SOR′. In another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —COOR′. In another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —CON(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In another embodiment, R¹ and R², taken together is optionally substituted azocan-1-yl (hh), wherein z is 1 and R⁴ is —COR′.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet another embodiment, each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In another embodiment, each occurrence of R³ is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In another embodiment, R³ is independently selected —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R³ is independently selected from —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, R³ is —CON(R′)₂, or —NRCOR′.

In one embodiment, y is 0-5. In another embodiment, y is 0. Or, y is 1-3. In another embodiment, y is 1-2. Or, y is 1.

In one embodiment, R⁵ is independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In another embodiment, R⁵ is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In another embodiment, R⁵ is F. Or, R⁵ is OR′. In one embodiment, R⁵ is OH.

In one embodiment, the present invention provides a compound of formula I-i-A, formula I-ii-A, or formula I-iii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-iv-A, formula I-v-A, or formula I-vi-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-vii-A, formula I-viii-A, or formula I-ix-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-x-A, formula I-xi-A, or formula I-xii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-xiii-A:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, y is 0.

In another embodiment, R³ is hydrogen.

In another embodiment, R³ is X—R^(Q) and X is a C1-C6 alkylidene. In another embodiment, X is a C1-C4 alkylidene. Or, X is —CH₂—.

In one embodiment, R^(Q) is independently selected from —R′, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂.

In another embodiment R^(Q) is R′.

In one embodiment, R³ is independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet another embodiment, each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from piperidinyl, piperazinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In another embodiment, each occurrence of R³ is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet another embodiment, each R³ is independently —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In another embodiment, R³ is independently selected —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R³ is independently selected from —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, R³ is —CON(R′)₂, or —NRCOR′.

In one embodiment, the present invention provides a compound of formula I-i-B, formula I-ii-B, or formula I-iii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-iv-B, formula I-v-B, or formula I-vi-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-vii-B, formula I-viii-B, or formula I-ix-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-x-B, formula I-xi-B, or formula I-xii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

In one embodiment, the present invention provides a compound of formula I-xiii-B:

wherein R¹, R², R³, R⁵, and y are as defined above.

Exemplary compounds of formula I are shown below in Table 1:

TABLE 1  1  2  3

 4  5  6

 7  8  9

10 11 12

13 14 15

16 17

4. General Synthetic Methodology

The compounds of this invention may be prepared in general by methods known to those skilled in the art. Exemplary synthetic routes are illustrated below for the preparation of the compounds of the present invention.

Compounds of formula I-i may be prepared as illustrated below in Scheme 1.

Conditions: a) Br₂, MeOH; b) 1. Et₃N, DMF, heat

Compounds of formula I-i may also be prepared as illustrated below in Scheme 1a.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat

Compounds of formula I-ii may be prepared as illustrated below in Scheme 2.

Conditions: a) Et₃N, THF, heat

Compounds of formula I-ii may also be prepared as illustrated below in Scheme 2a-1.

Conditions: a) Et₃N, THF, heat

Compounds of formula I-iii may be prepared as illustrated below in Scheme 3.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, Br, or F, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, Br, or F, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For X═Cl, CCl₃, or imidazolyl, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Conditions: a) Et₃N, THF, heat; b) deprotect: 1:1 TFA/DCM, rt, for Boc; H₂, Pd/C for Bn; NaOH for Bz, TBAF for R₃Si, etc.; c) For acid halides, DCM or THF, Et₃N; for carboxylic acids, EDC, HOBt, Et₃N, DMF; for X═OR′, THF or DMF, heat.

Compounds of formula I-iii may be prepared as illustrated below in Scheme 3.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat, 10 h

Compounds of formula I-iii may also be prepared as illustrated below in Scheme 3a.

Conditions: a) Br₂, MeOH; b) Et₃N, DMF, heat

Compounds of formula I-iv may be prepared as illustrated below in Scheme 4.

Conditions: a) HBTU, DIEA, DMF; b) NaOMe-MeOH-THF

Compounds of formula I-iv may be prepared as illustrated below in Scheme 4a.

Conditions: a) HBTU, DIEA, DMF; b) NaOMe, MeOH, THF

Compounds of formula I-v may be prepared as illustrated below in Scheme 5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) HNR¹R², DMF heat

Compounds of formula I-v may also be prepared as illustrated below in Scheme 5a.

Conditions: a) PdCl₂(dppf), Na₂CO₃, toluene, 140° C.; b) HNR¹R², DMF, heat.

Compounds of formula I-vi may be prepared as illustrated below in Scheme 6.

Conditions: a) p-TsOH, CH₂Cl₂; b) Zn(Cu), CH₂I₂, THF, heat

Compounds of formula I-vi may also be prepared as illustrated below in Scheme 6a.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R², acetone; ii. MeI; c) Zn(Cu), CH₂I₂, 12, THF, heat.

Compounds of formula I-vii may be prepared as illustrated below in Scheme 7.

Conditions: a) Et₃N, Dioxane-Ethanol, heat

Compounds of formula I-vii may also be prepared as illustrated below in Scheme 7a.

Conditions: a) Et₃N, dioxane, ethanol, heat

Compounds of formula I-viii may be prepared as illustrated below in Scheme 8.

Conditions: a) NaOMe, methanol, heat

Compounds of formula I-viii may also be prepared as illustrated below in Scheme 8a.

Conditions: a) HNR¹R², DMF; b) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O

Compounds of formula I-ix may be prepared as illustrated below in Scheme 9.

Conditions: a) Nitrosoguanidine, THF; b) 220° C.

Compounds of formula I-ix may be prepared as illustrated below in Scheme 9a.

Conditions: a) NaOH, ethanol, H₂O, heat

Compounds of formula I-x may be prepared as illustrated below in Scheme 10.

Conditions: a) NaH, THF, MeI, CS₂; b) NH₂OH, HNR¹R²

Compounds of formula I-xi may be prepared as illustrated below in Scheme 11.

Conditions: a) H₂O₂, ethanol-H₂O, heat

Compounds of formula I-xi may also be prepared as illustrated below in Scheme 11a.

Conditions: a) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; b) HNR¹R², DMF

Compounds of formula I-xii may be prepared as illustrated below in Scheme 12.

Conditions: a) NaOH, ethanol-H₂O, heat

Compounds of formula I-xii may also be prepared as illustrated below in Scheme 12a.

Conditions: a) NaOH, H₂O; b) 220° C.

Compounds of formula I-xiii may be prepared as illustrated below in Scheme 13.

Conditions: a) Et₃NR¹R²NH, DMF; b) Ethanol, 0° C.-25° C.

Compounds of formula I-xiii may also be prepared as illustrated below in Scheme 13a.

Conditions: a) Et₃N, R¹R²NH, DMF; b) ethanol, 0° C.-25° C.

Compounds of formula I-i-A may be prepared as illustrated below in Scheme A-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-ii-A may be prepared as illustrated below in Scheme A-2.

Conditions: a) i. Et₃N, THF, heat; ii. deprotect

Compounds of formula I-ii-A may also be prepared as illustrated below in Scheme A-2-1.

Conditions: a) i. Et₃N, THF, heat; ii. Deprotect.

Compounds of formula I-iii-A may be prepared as illustrated below in Scheme A-3.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat, 10 h; ii. deprotect

Compounds of formula I-iii-A may also be prepared as illustrated below in Scheme A-3-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-iv-A may be prepared as illustrated below in Scheme A-4.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe-MeOH-THF; ii. deprotect

Compounds of formula I-iv-A may also be prepared as illustrated below in Scheme A-4-1.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe, MeOH, THF; ii. deprotect

Compounds of formula I-v-A may be prepared as illustrated below in Scheme A-5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) i. HNR¹, R², DMF heat; ii. deprotect

Compounds of formula I-v-A may also be prepared as illustrated below in Scheme A-5-1.

Compounds of formula I-vi-A may be prepared as illustrated below in Scheme A-6.

Conditions: a) p-TsOH, CH₂Cl₂; b) i. Zn(Cu), CH₂I₂, THF, heat; ii. deprotect

Compounds of formula I-vi-A may also be prepared as illustrated below in Scheme A-6-1.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R², acetone; ii. MeI; c) i. Zn(Cu), CH₂I₂, I₂, THF, heat; ii. Deprotect.

Compounds of formula I-vii-A may be prepared as illustrated below in Scheme A-7.

Conditions: a) i. Et₃N, Dioxane-Ethanol, heat; ii. deprotect

Compounds of formula I-viii-A may be prepared as illustrated below in Scheme A-8.

Conditions: a) i. NaOMe, methanol, heat; ii. deprotect

Compounds of formula I-viii-A may also be prepared as illustrated below in Scheme A-8-1.

Conditions: a) HNR¹R², DMF; b) i. Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; ii. deprotect

Compounds of formula I-ix-A may be prepared as illustrated below in Scheme A-9.

Conditions: a) Nitrosoguanidine, THF; b) i. 220° C.; ii. deprotect

Compounds of formula I-ix-A may also be prepared as illustrated below in Scheme A-9-1.

Conditions: a) i. NaOH, ethanol, H₂O, heat; ii. Deprotect.

Compounds of formula I-x-A may be prepared as illustrated below in Scheme A-10.

Conditions: a) i. NaOH, methanol, heat; ii. deprotect

Compounds of formula I-x-A may also be prepared as illustrated below in Scheme A-10-1.

Conditions: a) NaH, THF, MeI, CS₂; b) NH₂OH, HNR¹R²

Compounds of formula I-xi-A may be prepared as illustrated below in Scheme A-11.

Conditions: a) i. H₂O₂, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xi-A may also be prepared as illustrated below in Scheme A-11-1.

Conditions: a) Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; b) i. HNR¹R², DMF; ii. deprotect.

Compounds of formula I-xii-A may be prepared as illustrated below in Scheme A-12.

Conditions: a) i. NaOH ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xii-A may also be prepared as illustrated below in Scheme A-12-1.

Conditions: a) NaOH, H₂O; b) i. 220° C.; ii. deprotect.

Compounds of formula I-xiii-A may be prepared as illustrated below in Scheme A-13.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. Ethanol, 0° C.-25° C.; ii. deprotect

Compounds of formula I-xiii-A-1 may be prepared as illustrated below in Scheme A-13-1.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. ethanol, 0° C.-25° C.; ii. deprotect

Compounds of formula I-i-B may be prepared as illustrated below in Scheme B-1.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat; ii. deprotect

Compounds of formula I-ii-B may be prepared as illustrated below in Scheme B-2.

Conditions: a) i. Et₃N, THF, heat; ii. deprotect

Compounds of formula I-iii-B may be prepared as illustrated below in Scheme B-3.

Conditions: a) Br₂, MeOH; b) i. Et₃N, DMF, heat, 10 h; ii. deprotect

Compounds of formula I-iv-B may be prepared as illustrated below in Scheme B-4.

Conditions: a) HBTU, DIEA, DMF; b) i. NaOMe-MeOH-THF; ii. deprotect

Compounds of formula I-v-B may be prepared as illustrated below in Scheme B-5.

Conditions: a) PdCl₂(dppf), Na₂CO₃, Tol, 140° C.; b) i. HNR¹R², DMF heat; ii. deprotect

Compounds of formula I-v-B may also be prepared as illustrated below in Scheme B-5-1.

Conditions: a) PdCl₂(dppf), Na₂CO₃, toluene, 140° C.; b) i. HNR¹R², DMF heat; ii. deprotect.

Compounds of formula I-vi-B may be prepared as illustrated below in Scheme B-6.

Conditions: a) p-TsOH, CH₂Cl₂; b) i. Zn(Cu), CH₂I₂, THF, heat; ii. deprotect

Compounds of formula I-vi-B may also be prepared as illustrated below in Scheme B-6-1.

Conditions: a) i. PCl₅, CH₂Cl₂; ii. NaSCN, acetone; b) i. HNR¹R², acetone; ii. MeI; c) i. Zn(Cu), CH₂I₂, I₂, THF, heat; ii. deprotect.

Compounds of formula I-vii-B may be prepared as illustrated below in Scheme B-7.

Conditions: a) i. Et₃N, Dioxane-Ethanol, heat; ii. deprotect

Compounds of formula I-viii-B may be prepared as illustrated below in Scheme B-8.

Conditions: a) i. NaOMe, methanol, heat; ii. deprotect

Compounds of formula I-viii-B may be prepared as illustrated below in Scheme B-8-1.

Conditions: a) HNR¹R², DMF; b) i. Pd(Ph₃)₄, K₂CO₃, CH₃CN, H₂O; ii. deprotect.

Compounds of formula I-ix-B may be prepared as illustrated below in Scheme B-9.

Conditions: a) Nitrosoguanidine, THF; b) i. 220° C.; ii. deprotect

Compounds of formula I-ix-B may also be prepared as illustrated below in Scheme B-9-1.

Conditions: a) i. NaOH, ethanol, H₂O, heat; ii. deprotect

Compounds of formula I-x-B may be prepared as illustrated below in Scheme B-10.

Conditions: a) i. NaOH, methanol, heat; ii. deprotect

Compounds of formula I-x-B may also be prepared as illustrated below in Scheme B-10-1.

Compounds of formula I-xi-B may be prepared as illustrated below in Scheme B-11.

Conditions: a) i. H₂O₂, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xi-B may also be prepared as illustrated below in Scheme B-11-1.

Compounds of formula I-xii-B may be prepared as illustrated below in Scheme B-12.

Conditions: a) i. NaOH, ethanol-H₂O, heat; ii. deprotect

Compounds of formula I-xii-B may be prepared as illustrated below in Scheme B-12-1.

Compounds of formula I-xiii-B may be prepared as illustrated below in Scheme B-13.

Conditions: a) Et₃N, R¹R²NH, DMF; b) i. Ethanol, 0° C.-25° C.; ii. deprotect

Compounds of formula I-xiii-B-1 may be prepared as illustrated below in Scheme B-13-1.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that are inhibitors of voltage-gated sodium ion channels and/or calcium channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium ion channel or calcium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain embodiments, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In certain other embodiments, a method for the treatment or lessening the severity of radicular pain, sciatica, back pain, head pain, or neck pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In still other embodiments, a method for the treatment or lessening the severity of severe or intractable pain, acute pain, postsurgical pain, back pain, tinnitis or cancer pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitis or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium ion channels or calcium channels, preferably N-type calcium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediated condition or disorder”. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.

In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”. For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXAMPLE Benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (9)

A solution of benzyl 4-thiocarbamoylpiperazine-1-carboxylate (2.7 g, 9.7 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (2.1 g, 9.7 mmol), diisopropyl ethylamine (1.9 mL, 11 mmol), and THF (32 mL) was sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 20 seconds. The reaction was cooled to room temperature, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO₂, 0%-30% EtOAc/hexanes) to give benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (1.05 g, 27% yield). LC/MS: m/z 398.3 (M+H)⁺ at 3.84 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

1-(4-(2-Fluorophenyl)thiazol-2-yl)piperazine

To a solution of benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (0.85 g, 2.1 mmol) in CH₂Cl₂ (2 μL) cooled to −50° C. was added boron tribromide (1 M in CH₂Cl₂, 8.6 mL, 8.6 mmol). The reaction was stirred at −50° C. for 20 min and then carefully quenched with saturated aqueous NaHCO₃. The mixture was extracted with CH₂Cl₂, and the combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to yield 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine. LC/MS: m/z 264.1 (M+H)⁺ at 2.04 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (10)

A solution of 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine (0.13 g, 0.50 mmol), triethylamine (0.10 mL, 0.75 mmol), and CH₂Cl₂ (1.7 mL) was cooled in an ice bath, and isobutyl chloroformate (0.10 mL, 0.75 mmol) was added. The reaction was stirred at 0° C. for 20 min, diluted with CH₂Cl₂, washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yield isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate. LC/MS: m/z 364.1 (M+H)⁺ at 3.87 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate

A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.21 g, 1.1 mmol), isobutyl piperidin-4-ylcarbamate (0.23 g, 1.2 mmol), and DMF (2 mL) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for two minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to yield isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 365.0 (M+H)⁺ at 3.20 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (20)

A mixture of isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (0.38 g, 1.1 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (0.35 g, 1.6 mmol), Pd(Ph₃)₄ (12 mg, 11 μmol), K₂CO₃ (0.29 g, 2.1 mmol), CH₃CN (3.0 mL), and H₂O (0.3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 175° C. for 15 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yield isobutyl 1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 377.3 (M+H)⁺ at 3.77 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

3-Chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole

A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh₃)₄ (11 mg, 9.3 mmol), K₂CO₃ (0.26 g, 1.9 mmol), and CH₃CN (3 mL containing 10% H₂O) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to yield 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)⁺ at 3.45 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

1-(5-(2-Methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine

A mixture of 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole (0.21 g, 0.93 mmol), piperazine (400 mg, 4.65 mmol), and DMF (3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 5 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to yield 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine. LC/MS: m/z 277.1 (M+H)⁺ at 2.19 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate

To a mixture of 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine (80 mg, 0.29 mmol) and triethylamine (61 μL, 0.43 mmol) in CH₂Cl₂ (0.5 mL) at 0° C. was added isobutyl chloroformate (59 mg, 0.43 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture was stirred at 0° C. for 1 h, diluted with water, and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to yield isobutyl 4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate. LC/MS: m/z 377.5 (M+H)⁺ at 3.81 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isobutyl 4-(5-(2-hydroxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (21)

To isobutyl 4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate from above was added boron tribromide solution (1 M in CH₂Cl₂, 1.7 mL, 1.7 mmol) at −30° C. The reaction mixture was stirred at −30° C. for 1 h and at room temperature for 3 h. To this mixture was added boron tribromide (1 M in CH₂Cl₂, 1.4 mL, 1.4 mmol), and the reaction was stirred for another hour. The reaction mixture was diluted with saturated NaHCO₃ and extracted with CH₂Cl₂. The combined extracts were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to give a residue which was filtered and purified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to yield isobutyl 4-(5-(2-hydroxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate. LC/MS: m/z 363.3 (M+H)⁺ at 3.52 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Representative analytical data is shown below in Table 2 for the compounds of the present invention.

TABLE 2 LC-MS LC-RT Cmpd. No. M + 1 min 1 260.8 3.54 2 362.2 3.85 3 376.3 3.29 4 382.2 3.65 5 360.2 2.98 6 348.3 3.66 7 376.5 3.22 8 364.3 3.23 9 398.3 3.84 10 364.1 3.87 11 378.2 4.19 12 378.2 3.34 13 366.0 3.36 14 362.3 2.89 15 391.1 3.23 16 377.3 3.77 17 363.3 3.52

Assays for Detecting and Measuring NaV Inhibition Properties of Compound

Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. Antagonist properties of test compounds were assessed as follows. Cells expressing the NaV of interest were placed into microtiter plates. After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with either a chemical or electrical means to evoke a NaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a decreased membrane potential response to the stimulus. The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (ee Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing a NaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coated plates at 60,000 cells per well. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

1) On the day of the assay, medium is aspirated and cells are washed twice with 225 μL of Bath Solution #2 (BS#2).

2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin stock solution with 10% Pluronic 127 1:1 and then dissolving the mix in the appropriate volume of BS#2.

3) After bath solution is removed from the 96-well plates, the cells are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated in the dark for 30 minutes at room temperature.

4) While the cells are being stained with coumarin, a 15 μL oxonol solution in BS#2 is prepared. In addition to DiSBAC₂(3), this solution should contain 0.75 mM ABSC1 and 30 μL veratridine (prepared from 10 mM EtOH stock, Sigma #V-5754).

5) After 30 minutes, CC2-DMPE is removed and the cells are washed twice with 225 μL of BS#2. As before, the residual volume should be 40 μL.

6) Upon removing the bath, the cells are loaded with 80 μL of the DiSBAC₂(3) solution, after which test compound, dissolved in DMSO, is added to achieve the desired test concentration to each well from the drug addition plate and mixed thoroughly. The volume in the well should be roughly 121 μL. The cells are then incubated for 20-30 minutes. 7) Once the incubation is complete, the cells are ready to be assayed on VIPR® with a sodium addback protocol. 120 μL of Bath solution #1 is added to stimulate the NaV dependent depolarization. 200 μL tetracaine was used as an antagonist positive control for block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460{nm}} - {background}_{460\;{nm}}} \right)}{\left( {{intensity}_{580{nm}} - {background}_{580{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated. For the Na⁺ addback analysis time windows, baseline is 2-7 sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$ where R is the ratio response of the test compound Solutions [mM] Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4 with NaOH Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 with KOH (final K concentration ˜5 mM) CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20° C. DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C. ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at room temperature Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL #10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are grown in vented cap flasks, in 90% humidity and 10% CO₂, to 100% confluence. They are usually split by trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the next split.

C) VIPR® Optical Membrane Potential Assay Method with Electrical Stimulation

The following is an example of how NaV1.3 inhibition activity is measured using the optical membrane potential method#2. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂0

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10 mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a 10 μM final staining concentration. The cells are stained for 30 minutes in the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The required amount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixed with 1 μL 10% pluronic for each mL of solution to be made and vortexed together. Then HBSS/HEPES is added to make up 2× solution. Finally, the ABSC1 is added.

The 2× DiSBAC₂(3) solution can be used to solvate compound plates. Note that compound plates are made at 2× drug concentration. Wash stained plate again, leaving residual volume of 50 μL. Add 50 uL/well of the 2× DiSBAC₂(3) w/ ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT/US01/21652, herein incorporated by reference. The instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mM glucose, pH 7.40, 330 mOsm

Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

1. Insert or use electrodes into each well to be assayed.

2. Use the current-controlled amplifier to deliver stimulation wave pulses for 3 s. Two seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities. Five seconds of post-stimulation recording are performed to examine the relaxation to the resting state. Data Analysis

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460{nm}} - {background}_{460{nm}}} \right)}{\left( {{intensity}_{580{nm}} - {background}_{580{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$ where R is the ratio response of the test compound. Electrophysiology Assays for NaV Activity and Inhibition of Test Compounds

Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culture media consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter) have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound's IC50 holding the cells at −60 mV. In addition, the “current clamp” mode has been employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (˜22° C.) with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (−7 mV) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +10 mV once every 60 seconds. Blocking effects were allowed to plateau before proceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA (1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33), KH2PO4 (0.44), MgCl2 (0.5), MgSO4 (0.41), NaHCO3 (4), Na2HPO4 (0.3), glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

CURRENT-CLAMP Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp 700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filled with (in mM): 150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂, (buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl, 3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroed before seal formation; liquid junction potentials were not corrected during acquisition. Recordings were made at room temperature.

The activity of selected compounds of the present invention against NaV 1.8 channel is shown below in Table 3. In Table 3, the symbols have the following meanings: “+++” means <10 μM; “++” means between 10 μM and 20 μM; and “+” means >20 μM.

TABLE 3 Compound # IC₅₀ 1 ++ 2 + 3 ++ 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 + 

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

 is a single or double bond; X₁ is —S—; X₂ is ═CR³—; X₃ is a lone pair of electrons; provided that X₁, X₂, and N(X₃), taken together with the intervening carbon atoms form a 5-membered heteroaryl ring; W is halogen or OR′; R¹ and R², taken together with the nitrogen atom, form a piperidinyl ring (cc) or a piperazinyl ring (dd):

wherein z is 0-5; y is 0; R³ is hydrogen; R⁴ is Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain and R^(X) is selected from —NR′COR′, —NR′CO₂R′, —COR′, —CO₂R′, or —SO₂R′; R⁵ is halogen; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 2. A compound according to claim 1, wherein R¹ and R² taken together form a piperazinyl ring:


3. The compound according to claim 1, wherein R¹ and R² together form a ring as shown below:

wherein R^(XX) is C1-C6 alkyl.
 4. The compound according to claim 3, wherein R^(XX) is methyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.
 5. The compound according to claim 1, wherein R¹ and R² taken together form ring (kk) as shown below:

G₃ is —N—, or CH; each of m₂ and n₂ is 2; p₂ is 0-2; provided that when G₃ is N, then p₂ is not 0; q is 0 or 1; z is 0-4; Sp is a bond or a C1-C6 alkylidene linker; ring B is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-3 heteroatoms selected from O, S, or N, wherein ring B is optionally substituted with w independent occurrences of —R¹², wherein w₂ is 0-4; each occurrence of R¹² is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain; and each occurrence of R^(X) is independently selected from —NR′COR′, —NR′CO₂R′, —COR′, —CO₂R′ or —SO₂R′; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents.
 6. The compound according to claim 1, wherein R¹ and R² taken together form a ring (ll):

wherein: each of m₃ and n₃ is 2; z is 0-4; Sp³ is —O—, or a C1-C6 alkylidene linker, ring B₃ is a 4-8 membered, saturated, partially unsaturated, or aromatic, monocyclic heterocyclic ring having 1-3 heteroatoms selected from O, S, or N, wherein ring B₃ is optionally substituted with w independent occurrences of —R¹³, wherein w₃ is 0-4; each occurrence of R¹³ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain; and each occurrence of R^(X) is independently selected from NR′COR′, —NR′CO₂R′, —COR′, —CO₂R′; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents.
 7. The compound according to claim 1, wherein R¹ and R² taken together form a ring (mm):

wherein: each of m₄ and n₄ is 2; p₄ is 1-2; R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄ independent occurrences of —R¹⁴, wherein w₄ is 0-3; each occurrence of R¹⁴ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain; and each occurrence of R^(X) is independently selected from NR′COR′, —NR′CO₂R′, —COR′, —CO₂R′, or —SO₂R′; and each occurrence of R is independently hydrogen or C₁₋₆ aliphatic group having up to three substituents; and each occurrence of R′ is independently hydrogen or C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R′ has up to four substituents.
 8. The compound according to claim 1, wherein W is OR′.
 9. The compound according to claim 8, wherein W is OH.
 10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable adjuvant or carrier.
 11. A compound according to claim 1, wherein said compound is selected from the group consisting of the following compounds: 